CN100444782C - Method and device for the quantitative analysis of solutions and dispersions by means of near infrared spectroscopy - Google Patents
Method and device for the quantitative analysis of solutions and dispersions by means of near infrared spectroscopy Download PDFInfo
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- CN100444782C CN100444782C CNB2004800157801A CN200480015780A CN100444782C CN 100444782 C CN100444782 C CN 100444782C CN B2004800157801 A CNB2004800157801 A CN B2004800157801A CN 200480015780 A CN200480015780 A CN 200480015780A CN 100444782 C CN100444782 C CN 100444782C
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- insulin
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Images
Classifications
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
- G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
- G01N21/31—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
- G01N21/35—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light
- G01N21/3563—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light for analysing solids; Preparation of samples therefor
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01J—MEASUREMENT OF INTENSITY, VELOCITY, SPECTRAL CONTENT, POLARISATION, PHASE OR PULSE CHARACTERISTICS OF INFRARED, VISIBLE OR ULTRAVIOLET LIGHT; COLORIMETRY; RADIATION PYROMETRY
- G01J3/00—Spectrometry; Spectrophotometry; Monochromators; Measuring colours
- G01J3/02—Details
- G01J3/0205—Optical elements not provided otherwise, e.g. optical manifolds, diffusers, windows
- G01J3/0218—Optical elements not provided otherwise, e.g. optical manifolds, diffusers, windows using optical fibers
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01J—MEASUREMENT OF INTENSITY, VELOCITY, SPECTRAL CONTENT, POLARISATION, PHASE OR PULSE CHARACTERISTICS OF INFRARED, VISIBLE OR ULTRAVIOLET LIGHT; COLORIMETRY; RADIATION PYROMETRY
- G01J3/00—Spectrometry; Spectrophotometry; Monochromators; Measuring colours
- G01J3/02—Details
- G01J3/0205—Optical elements not provided otherwise, e.g. optical manifolds, diffusers, windows
- G01J3/024—Optical elements not provided otherwise, e.g. optical manifolds, diffusers, windows using means for illuminating a slit efficiently (e.g. entrance slit of a spectrometer or entrance face of fiber)
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01J—MEASUREMENT OF INTENSITY, VELOCITY, SPECTRAL CONTENT, POLARISATION, PHASE OR PULSE CHARACTERISTICS OF INFRARED, VISIBLE OR ULTRAVIOLET LIGHT; COLORIMETRY; RADIATION PYROMETRY
- G01J3/00—Spectrometry; Spectrophotometry; Monochromators; Measuring colours
- G01J3/12—Generating the spectrum; Monochromators
- G01J3/18—Generating the spectrum; Monochromators using diffraction elements, e.g. grating
- G01J3/1804—Plane gratings
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01J—MEASUREMENT OF INTENSITY, VELOCITY, SPECTRAL CONTENT, POLARISATION, PHASE OR PULSE CHARACTERISTICS OF INFRARED, VISIBLE OR ULTRAVIOLET LIGHT; COLORIMETRY; RADIATION PYROMETRY
- G01J3/00—Spectrometry; Spectrophotometry; Monochromators; Measuring colours
- G01J3/28—Investigating the spectrum
- G01J3/2803—Investigating the spectrum using photoelectric array detector
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
- G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
- G01N21/31—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
- G01N21/35—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light
- G01N21/359—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light using near infrared light
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/84—Systems specially adapted for particular applications
- G01N21/88—Investigating the presence of flaws or contamination
- G01N21/90—Investigating the presence of flaws or contamination in a container or its contents
- G01N21/9018—Dirt detection in containers
- G01N21/9027—Dirt detection in containers in containers after filling
Abstract
The present invention relates to a method for quantifying the composition of a product, with the following steps: irradiating the product with a radiation source in the near infrared range; receiving radiation which is reflected by or transmitted through the product, and providing an output signal corresponding to the intensity of the radiation received at a number of different wavelengths; determining whether or not the product lies within predetermined integrity criteria on the basis of the output signal using a mathematical method, wherein the product contains a solution or homogeneous dispersion, and the content of at least one substance contained in the dispersion or solution is quantitatively determined on the basis of the output signal., The present invention also relates to an apparatus for carrying out this method.
Description
Technical field
The present invention relates to a kind of near infrared spectrum that utilizes for solution and dispersion liquid, as be used for the solution and the dispersion liquid of pharmacy purpose, the method and apparatus that carries out quantitative analysis.
Background technology
Always wish to improve quality control to improve drug safety at pharmaceutical field.Simultaneously, (Current Good Manufacturing Practice cGMP) makes, and described standard is formulated (as U.S. food and drug administration, FDA) by medicine regulator according to international pharmaceutical production management regulation.If seriously violate this production management's standard, enterprise can be cancelled the pharmaceutical production permission.
A part and parcel of pharmaceutical production management regulation is dispatching from the factory of physical-chemical and microbiological test and finished product.In test process, detect the parameter of a plurality of these product qualities of description and itself and product specification are compared.These specifications or write into the certification adnexa or write in the International Pharmacopoeia.When all specifications are observed, then this product can come into the market.One of these detected parameters are to obtain quantitatively definite active substance content.Quantitatively determine and often to carry out with sampling method with the test of damage type.Preferentially use liquid chromatography or gas chromatography or also use spectrographic technique as analytical method, described method all needs to carry out sample preparation.The characteristics of these methods are that higher precision is arranged, but analysis speed is but very slow.Thus, these methods are not adapted on the production line, and that is to say directly provides the result at production period.
In addition, this measurement can't be carried out on the product in inner packing.
The shortcoming that this powder charge of carrying out with sample mode detects is, can't record trend in the product or unusual result, for example when the filling suspension.This exists such danger, and promptly medicine is delivered for use as product up to specification, although in fact it is not being paid within (specification) restricted portion.This " defective " (OOS)-product produces such as the product problem or mix by product of meeting by short-term.
For complete, the requirement that just each unit that produces on the production line of operation is detected with sampling mode, can only by non-destructive work and enough fast analytical method satisfy.These two kinds of requirements can be satisfied by spectroscopic analysis methods in principle.But the overwhelming majority of this method early stage not such as dissolving by sample, concentrate or the situation of the sample system standard of dilution under and be not suitable for providing quantitative analysis results.Common this method also is not suitable for, and sees through inner packaging material (such as glass or plastics) but and/or the spectrum of generation quantitative assessment in disperse system.Have only the narrower wave-length coverage of the 800-2500nm of near infrared ray (NIR) can be used to handle this generic task.
To the object monitoring that conveyer belt is carried, promptly carry out real-time and the method for monitoring fully basically, be known to the sorting of refuse classification or working of plastics.Described method has partly been used this near-infrared (NIR)-spectrogrph.
EP-B 1 030 740 discloses a kind of method that is used to discern the object of carrying with sorting conveyer, method especially for refuse classification, in this method, utilize the method for spectrum analysis to obtain the material behavior of object and carry out sorting by take off object from transport tape according to the spectrum analysis result by a kind of NIR-measuring instrument.
EP-B 0 696 236 discloses a kind of method that is used for separating plastic spare, and in the method, the guiding working of plastics is through a system for discriminating materials, and described system determines its material category by each material pieces in the measurement zone is carried out contactless scanning.This system for discriminating materials comprises the material sensors of a contactless job, such as a microwave remote sensor, and an X ray sensor or a spectrum sensor near infrared region work.
When being used for pharmacy purpose filling suspension, because the segregation process can be shaken in the process of filling.This unit that is loaded (as cartridge case) that may cause a part that shakes has active substance (as insulin) or auxiliary agent (as the Protamine sulfates .) content value that is in institute's specification limit that requires (nominal value as insulin is 95.0% to 105.0%) in addition.
European patent application EP-A 0 887 638 has described a kind of method and apparatus that is used for analyzing the constituent of motion sample, wherein adopts near-infrared (NIR)-irradiation source, and detects the NIR-ray by the sample reflection.As tablet on the sample analysis conveyer belt or capsule.
High pressure lipuid chromatography (HPLC) (HPLC, high pressure (performance) liquidchromatography) is applicable to the quantitative analysis liquid sample in principle.But by by means of HPLC such shortcoming being controlled in the quantitative analysis of sample, promptly this method slowly and not right and wrong is carried out devastatingly.Therefore it only is applicable to the quality control of sampling formula.It is contemplated that this method is not suitable for such quality control, whether the active substance content that promptly wherein will detect each product unit of filling is positioned within the specification requirement.
Herkert (2001, paper, Eberhard-Karls university, Thuringen) assesses the NIR-method that is used for medicine on the baling line and carries out quality control.Its target is especially to spectrogrph
(Uhlmann Visio Tec GmbH, assessment Laupheim).Wherein, assessment is carried out by means of insulin suspensions.
In the work of Herkert, indirect ray is detected, promptly detect the diffuse reflection ray of incident NIR ray.Wherein, only to three kinds in its constituent of forming by soluble and crystalline insulin different insulin types distinguish qualitatively.According to the spectrographic difference in original spectrum or branch spectrum, whether assessment can be discerned single product according to NIR spectrum.By means of PCA (PCA) or
-estimating statistics can carry out pattern recognition according to this difference.Wherein do not carry out quantitative analysis.Using under the situation of instrument with this on the baling line
-spectrometer measurement liquid (insulin suspensions) is impossible.The scattering effect with in the air space on glass above suspension has hindered correctly carries out spectrum record (paper of the Herkert of the face that sees before citation, 76 pages, the 2nd section).
Summary of the invention
The objective of the invention is, a kind of product analysis method is provided, described product comprises and for example is used for pharmacy purpose solution and dispersion liquid, utilize this analytical method to carry out rapid quantitative and determine contained material in the solution or in the dispersion liquid, and this method be not intrusive mood and the work of non-destructive ground.Especially this method is suitable in unit interval inner analysis large-tonnage product unit, the constituent of solution or dispersion liquid is controlled when for example being used in process of production on filling equipment or baling line filling.Here said control is meant that in real-time control, all product units have been contained in described control basically.
Find unexpectedly that now quantitative methods is carried out in the constituent of the product in can especially moving to product with following step application:
With the irradiation source that is in the near infrared range product is shone;
Reception is by ray product reflection or emission, and for the different wave length of some, and the corresponding output signal of intensity with the multi-wavelength's who is received ray is provided;
Utilize mathematical method to determine whether product is in predetermined whole standard according to this output signal
Within.
The method according to this invention is characterised in that, the product in the motion contain solution or uniformly dispersion liquid and according to this output signal quantitatively determine at least a dispersion liquid or solution in the content of material that comprises.
The quantitative meaning in the present invention is, comprise in solution or the dispersion liquid, be generally rated value (for example definite) by cover Lun Shi prescription ± 3%, preferably ± 5%, especially preferably ± 10%, the content of the material at least a to be determined in the scope especially ± 20% can be determined clearly and correctly.Be meant that clearly the numerical value that utilizes method of the present invention to determine is that wherein relative standard deviation is not higher than 1.5%, preferably is not higher than 1%, especially preferably is not higher than 0.5% reliably.Here, by means of effective and approved pedestal method, the chromatography as HPLC, determined reference value is regarded as correct, the mutual deviation of wherein said reference value and the determined numerical value of method of the present invention is a maximum 5%, is preferably 3%, is preferably 1% especially.
Product contains solution and dispersion liquid arbitrarily usually in the radiolucent container to NIR-.When this product contained dispersion liquid, then normally a kind of aqueous dispersions was as emulsion or suspension.This in dispersion liquid material contained, that its content is quantitatively determined with method of the present invention, can only be present in that continuous phase maybe can only be present in decentralized photo but or also can distribute in mutually and exist at these two kinds.At dispersion liquid or solution can be dissolving and/or the medical product that is dispersed with active substance.At the material that will quantitatively determine content can be the active substance or the auxiliary agent of for example medicine.For example solution can be insulin solutions, and dispersion liquid can be an insulin suspensions, this suspension is suspended with crystalline or unbodied insulin and contains dissolved insulin in addition sometimes, as NPH-type (the neutral goods that contain the Hagedom insulin of protamine), the mixture of NPH-insulin and dissolved insulin or insulin-zinc-float.Described insulin can be for example human insulin or its by the analog of genetic method or enzyme modification.
Solution or dispersion liquid can be present in inner packing
In, for example in cartridge case, ampoule or the medicine bottle that glass or plastics are made.Described packing can be on the conveyer belt, and is for example checking with method of the present invention in the transportation from the filling device to the packer.
Method of the present invention can be implemented with catoptric arrangement or transmission structure.In a kind of form of implementation of this method, carry out work with a kind of transmission structure, promptly receive ray by the product transmission.
Radiographic source with near infrared range shines the product that needs are carried out to the branch check.Common this near infrared range comprises 800 to 2500nm wave-length coverage.The light source that is suitable for for example has hydrargyrum-Halogen light.
Receive by a ray receiving system by the ray product reflection or transmission.For the different wavelength of some, the corresponding output signal of transmitted intensity that provides Yu received.This can be achieved like this, that is, in spectrogrph the light of penetrating that is received is divided into the wavelength of some and detects with photodiode arrangement.Can in a preset time section, quadrature (integrieren) by the electric current of each light sensitive diode, and be converted into digital signal by analog/digital (A/D)-transducer subsequently.
Can be according to the position of the product of motion by flip flop equipment-as photoelectricity fence (Lichtschranke)-the start time period of this integration.
According to the output signal that provides for different wave length, can utilize mathematical method quantitatively to determine the content of at least a material that comprised in dispersion liquid or the solution.The appropriate mathematical method is the method that is used for multivariate data analysis.Suitable method for example comprises PLS-method (partial least square method) or PCA (PCA).Described method is well known by persons skilled in the art.
Described mathematical method can adopt weight coefficient, so that in evaluation procedure, reduce interfering in the NIR-spectrum that is received and with the influence of the irrelevant variable of constituent, and outstanding spectrum characteristics, described feature can not change between the sample of like products type.
Usually, by quantitatively determine the content of at least a material in solution or the dispersion liquid by another kind of optional method, carry out primary calibration at least.
A kind of preferred optional method that is used to calibrate is HPLC.This calibration can repeat during enforcement the inventive method at regular intervals.
In a form of implementation of method of the present invention, used in EP-B 0 887 638 from 47 of page 5 and walked to mathematical method described in the 8th page 12 row.EP-B 0 887 638 therewith mutually the content of light intactly quote in this manual.In the mathematical method described in the document, adopted weight coefficient.
Here revised the former spectroscopic data of describing light intensity by interval (as 3.8nm), wherein obtained a standard value, the characteristic of this standard value and spectrogrph and ray receiving system is irrelevant.The intensity of calibrating is like this carried out smoothing processing,, wherein adopt Gauss's smooth function so that the influence of signal noise minimizes.For the influence that is caused by system is minimized, can carry out auto-scaling (autoskalieren) to described data.In addition, to be standardized as a standard deviation on overall wave-length coverage be that 0 and variance is 1 value to this spectrographic each intensity.By setting up first derivative, can draw the difference of each spectrum on slope and the spectral characteristic of each outturn sample.Also can adopt 2 rank or 0 order derivative to replace first derivative.
Subsequently for the difference between each measured wavelength computation model spectrum and this outturn sample spectrum (sample spectra).If this difference has surpassed the limit value of setting, then sample is identified as with model significant difference.
This model (master cast) is to be set up by the calibration data set (group) of the same sample of the some of different product types.Calculate a meansigma methods spectrum simultaneously.If observe the variation of the model of each measurement point (wavelength), just can find to have the spectral region of obviously higher standard deviation.Described scope reflects for the difference of the glass of different affecting factors-for example or the variation of difference-(having identical constituent) calibration sample of position in cartridge case.For the influence described disturbance variable drops to minimum, calculate weight coefficient.This weight coefficient is higher than the weighting of the spectral region with big standard deviation to the spectral region with less standard deviation.For each wavelength by intensity level between the standard deviation of spacing and the standard deviation of the intensity level of model obtain described weight coefficient.
Next, under the situation of using described weight coefficient, calculate the Euclidean distance of each concentrated data set of calibration sampled data.The meansigma methods of described value is corresponding to the standard deviation of model.Setting up the last average Euclidean distance of also wanting computation model of model.Given this value is as datum quantity in the model standard deviation.
In method implementation process of the present invention, spectrum and the described model spectrum that each outturn sample obtained is compared., calculate for this reason, wherein, adopt weight coefficient for each wavelength for the intensity of each wavelength and the Euclidean distance between the corresponding mold strength.The weight coefficient that is adopted obtains when setting up model.The result is used to the Euclidean distance of calculation sample.It is designated as datum quantity in the model standard deviation.
The Euclidean distance value of sample is finally compared with a fixed boundary value.This boundary value is by the average Euclidean distance of model and probable range and calculate.
Can test solution and the constituent of dispersion liquid in order to above-mentioned mathematical method.When checking the constituent of dispersion liquid, then in a particularly preferred embodiment of this method, in determining step, adopt the weight coefficient that obtains based on solution.At this moment, serve as that the basic solution that obtains weight coefficient preferably comprises treat the quantitatively definite material identical with dispersion liquid with it.Described material exists to dissolving in dispersion liquid dispersedly and additionally, perhaps-generally-distributing between successive phase and dispersive phase exists.
For example insulin suspensions contains the suspension insulin of some dissolved insulin and a part of crystalline state.When insulin content was constant, the insulin of this part crystalline state can change in the larger context.It is in this case, verified that to adopt the weight coefficient that obtains based on purified insulin solution in determining step be favourable.Can eliminate the influence of the dispersion effect that causes by the suspension crystallization body when adopting the weight coefficient of pure solution.
Utilizing described mathematical evaluation method, can be to carry out at a high speed the analysis of product, for example within a time window that has only 5ms.This makes can carry out a large amount of product analyses in the time period of a weak point.Described in addition method is non-intrusion type ground and works non-contactly.Therefore for example be fit to well to the product on the baling line analyze or be fit to be used for cartridge case or bottle filling device combine product analyzed.Described analysis can be carried out in real time and can measure 100% of the product carried on the baling line.Utilize the method per second of the present invention can be at least 3, preferred minimum 8 or even 50 or more products before and after sequentially analyze.Therefore, described method for example is suitable for making, filling and/or packing is carried out (quality) control to product unit when being used for the solution of pharmacy purpose and dispersion liquid.
Utilize method of the present invention for example passable, be used for pharmacy purpose solution or dispersion liquid filling process, can change 100% the control of product over to from the control of sampling product.
Content of the present invention also comprises, a kind of device of quantitative levels of at least a material of the product that is used for determining motion, and described product comprises solution or the dispersion liquid in the container, described device comprises:
An irradiation source, described irradiation source are transmitted in the ray in the near infrared range, with product irradiation;
Reception is by the ray receiving system of the ray of product reflection or transmission;
One be used for receiving from ray receive tipping put send ray and be used for different wave length for some spectrogrph with the corresponding output letter of the transmitted intensity that is received be provided;
The device that the content that is used at least a material that dispersion liquid or solution comprised according to output signal carries out quantitatively determining.
Described ray receiving system can have convex lens and optical fiber.Described spectrogrph can have photodiode arrangement as detector.
Described device preferably additionally also has a calibrating installation, utilizes described calibrating installation to determine the quantitative levels of at least a material, for example high pressure lipuid chromatography (HPLC) according to the optional method of another kind.
In addition, described device also can additionally have a sorting unit, utilizes described sorting unit can sub-elect the product that falls short of specifications that detects with method of the present invention.The product that falls short of specifications is meant the not product within the whole standard of predesignating.
If described device (going back) is used for the quantitative analysis of dispersion liquid, then described device comprises also that preferably is used for making a device for the treatment of quantitative dispersion liquid homogenization before dispersion liquid is analyzed.For example can in container, make described dispersion liquid homogenization by head motion or by rotating mechanism.But homogenization also can realize by the filling process.
Described device also can have a device that is used to discern product space, such as imaging system or photoelectricity fence.
Described device can be used in combination with filling device, in described filling device solution or dispersion liquid is loaded in the inner packing.Described device also can be the ingredient of described filling device.
In a form of implementation of the present invention, a kind of device is provided, the effect of described device is a light transmission, wherein said device has the optical fiber that the ray that will be launched by irradiation source is directed to the position of product.
The specific embodiment
Describe the present invention in detail below with reference to accompanying drawing.
The schematically illustrated device of the present invention of Fig. 1, this device is by transmission means work.This device comprises an irradiation source (1), for example tungsten-halogen lamp.Sight by convex lens (2) and be directed to product (4) by the near infrared ray of described irradiation source emission and locate by means of optical fiber (3).Described product for example can be the glass injection medicine bottle that contains float, and described product for example is directed the end of process optical fiber (3) at conveyer belt from filling device.
Give spectrogrph (6) by the ray that product (4) transmits by a convex lens (5) calibration and by means of fiber optic conduction.In spectrogrph (6), comprise the ray of the transmission of the spectral information of being penetrated the product of wearing (4), be divided into ray and detect by means of a grid (7) by a photodiode arrangement (8) with different wave length.Convert digital signal according to the detected intensity level of wavelength by an A/D-transducer (9) by photodiode arrangement, and in definite device (10)-for example in the PC-estimate.
Example 1
Insulin loaded to carry out (quality) monitoring purposes be that the insulin content of 100% the insulin ampoule that is loaded is quantitatively controlled.Here, the insulin content of the insulin suspensions of being loaded have only the deviation of maximum+/-5% with probe value.Should detect abnormal conditions like clockwork.
Monitoring for to the filling of simulation insulin utilizes one group to contain crystallization Insuman in inner packing
The calibration sample of-insulin is calibrated, and then outturn sample is checked.In order to calibrate, adopt insulin cartridge with accurately known insulin content of 90 to 120% for specified content.Utilize HPLC to determine reference value.Before measurement, cartridge case is shaken completely, there to be uniform suspension.
Utilize a photodiode arrangement-spectrogrph (MCS 511 NIR 1.7) in transmission, to receive insulin spectrum.The wave-length coverage of measuring is 960 to 1760nm, wherein 960 to 1360nm wave-length coverage is estimated.The Halogen light that adopts 20W is as the NIR-light source.Usually spectrogrph and base standard are compared.Adopt a BG5 wave filter and a BG9 wave filter as a reference.
For spectrum is carried out pretreatment, spectrum is carried out smoothing processing and standardization.Use described spectrum with 0 order derivative.This moment, the scattering properties of insulin sample remained in the spectrum.
Then, by multivariable evaluation methodology spectrum is estimated.Adopt PLS (partial least square method)-recurrence as the Return Law.Can certainly adopt other multivariate evaluation methodology.By returning, set up the spectral information of insulin sample and the mathematical relationship between the insulin content.By the insulin content that can from the spectrum of unknown sample, calculate this sample after the described relation.
Fig. 2 illustrate for
Dependency between the value of that-insulin-calibration sample is measured with HPLC and the insulin-total content of (recently the representing with the percentage of specified content respectively) of measuring by the NIR-transmission spectrum.As can be seen, there is good dependency between value that records by NIR-spectrum and the value that records with HPLC.
Then, the process sample from insulin-production process is studied.Described sample is to obtain in daily production process also as using and depleted sample.From NIR-spectrum, obtain content of insulin by means of multivariable regression equation.Then by HPLC studying to identical ampoule.
Fig. 3 illustrates determined insulin-total content with HPLC, and Fig. 4 illustrates the insulin-total content of institute's study sample (representing with IE respectively) of determining with illustrated in this manual evaluation methodology from NIR-spectrum.
From the NIR-transmission spectrum and with the value that HPLC obtains, demonstrate good concordance.Clearly, the abnormal conditions that record by HPLC fully can be by level and smooth detecting with standardized NIR-transmission spectrum.
Example 2
The purpose that quality monitoring is carried out in insulin filling is that the insulin content of 100% the insulin ampoule that loads is quantitatively controlled.Here, the numerical value of the insulin content of the insulin suspensions of being loaded and institute's nominal should have only the deviation of maximum+/-5%.Should detect abnormal conditions like clockwork.Monitoring should or be carried out on the insulin cartridge of motion during loading, and is perhaps carrying out on the insulin cartridge of having loaded after the filling.In both cases, measuring all is to carry out through inner package (glass ampoules) and in the testee of motion.
In order to simulate the speed that when loading insulin cartridge, exists, adopt the optics controller of EISAI Machinery company 288 types.This machine can be used insulin cartridge (suspension) filling, and can make described cartridge case rotation, thus by with injection bottle in the Metal Ball that contains form uniform suspension.The NIR-measuring device is installed in this machine, and its structure is referring to shown in Figure 1.Measurement with the efficient of 150 bottles of per minutes motion, be in the cartridge case in the rotation and carry out.Here be noted that in measurement and have uniform suspension constantly.The measuring device of being installed is by the Halogen light (Comar 12LL50) of a 50W, a retainer (for example Comar 20LH00) that is used to have the lamp of the integrated convex lens that the focus of ray can be focused on the insulin cartridge center, one second convex lens (for example Comar 80TC50), the ray that the calibration of described second convex lens is transmitted and by a bonder (Zeiss for example, Nr.772571-9020-000) and an optical fiber (as Zeiss, CZ-#1050-724) described ray is flowed to a photodiode arrangement-detector (Zeiss, MMSNIR NR.301261).The analogue signal at detector place is carried out digitized and it is read in the text.On about 900 to 1670nm scopes, measuring ray on 128 light sensitive diodes altogether.The moment of measuring is by photoelectricity fence (Wenglor, a UM55PA2; 083-101-202) trigger, described photoelectric sensor is controlled spectrographic record during by ray channel at cartridge case.The PDA-detector is measured at each and is at first compared with Spektralon day.
Measured the insulin preparations (suspension) of Insuman Basal, Insuman Comb 25 and InsumanComb 50 types with described device.The duration of spectrum record is 8 milliseconds [ms].
Utilize described in this manual method contrast model spectrum that insulin spectrum is estimated.Model spectrum and its variability are measured by the cartridge case that water is housed to 8 and are obtained.Described model spectrum and insulin spectrum are carried out smoothing processing and auto-scaling.Next under the situation that adopts the distinctive weight coefficient of wavelength, calculate the Euclidean distance between each insulin spectrum and the averaging model spectrum.
For every kind of insulin preparations type i nsuman Basal, Insuman Comb 25 and Insuman Comb 50, the preparation samples of different concentrations, and calculate the spectrographic Euclidean distance of model.In Fig. 5, be that example exemplarily illustrates with Insuman Comb 25, for different product type, the dependency of insulin content and Euclidean distance.Wherein it can also be seen that the precision of this method, because show repeated measure 4 times.Draw a calibration function (second order polynomial) for each product type, utilize this function Euclidean distance can be converted into insulin content.After Euclidean distance is converted into insulin content, must consider two correction coefficients.Must proofread and correct described insulin content at the temperature of measured object.Also can additionally use a distinctive coefficient of goods, described coefficient derives from crystalline solid distribution of sizes different in the suspension.Therefore also can represent content with percentage ratio according to first 20 results.This moment is according to first cartridge case of one-time pad, just can obtain described content with the form of the percentage ratio of rated value.On the other hand, measured insulin content also can be proofreaied and correct at a factor/coefficient, and described coefficient is drawn by the ratio of the uncorrected value of sample with the insulin content of parallel measurement.In Fig. 6, utilize sample 16 to obtain described correction coefficient, and exemplarily the cartridge case of a series of unknown content of other product type of Insuman Comb25 is estimated by this way.Here adopt be in daily production process, obtained and as the depleted sample of defective work.The correction coefficient that does not have serviceability temperature is not because (temperature) has difference in estimating process.Other sample is analyzed with HPLC in the mode of sampling.
Can see, consistent with result's (black quadrangle) that method of the present invention drew and the result who obtains by traditional method (HPLC, black fork).No matter a value be within 95 to 105% the boundary or outside, can estimate clearly and accurately.
Claims (24)
1. be used for quantized method is carried out in the constituent of product of motion, may further comprise the steps:
With the irradiation source product irradiation in the near infrared range;
Receive to see through the ray of product transmission, and, provide the corresponding output signal of intensity with the ray that is received for the different wave length of some;
According to described output signal, utilize mathematical method to determine whether product is within the whole standard of predesignating,
It is characterized in that the product in the described motion comprises solution or uniform dispersion liquid, and quantitatively determine at least a content that is included in the material in described dispersion liquid or the solution according to described output signal.
2. according to the method for claim 1, it is characterized in that described at least a material is with the dispersive phase of dispersion liquid and/or successively exist mutually.
3. according to the method for claim 1, it is characterized in that, quantitatively determine in the solution or the content of the described at least a material in the dispersion liquid, carry out primary calibration at least by utilizing another optional method.
4. according to the method for claim 3, it is characterized in that, adopt high pressure lipuid chromatography (HPLC) as described other optional method.
5. according to the method for claim 1, it is characterized in that described determining step is utilized weight coefficient.
6. according to the method for claim 5, it is characterized in that, described product comprises a kind of dispersion liquid, and adopts the weight coefficient that obtains based on solution in determining step, and the solution that is used to obtain weight coefficient contains identical pending quantitatively definite material with dispersion liquid.
7. according to the method for claim 6, it is characterized in that the described material that is included in the dispersion liquid exists with dispersive mutually with successive phase.
8. according to the method for claim 1, it is characterized in that described product contains the dispersion liquid that comprises crystalline and/or dissolved insulin.
9. according to the method for claim 1, it is characterized in that the product of described motion is solution or the dispersion liquid in a kind of inner packing.
10. according to the method for claim 1, it is characterized in that the product of described motion is a kind of insulin ampoule or insulin cartridge.
11. the device of the quantitative levels of at least a material in the product that is used for determining to move, described product comprises solution or the homodisperse liquid in the container, and described device comprises
An irradiation source, described irradiation source divergent-ray near infrared range is with product irradiation;
The ray receiving system of the ray of product transmission is reflected or is seen through in a reception by product;
One is used to receive from the ray of ray receiving system and is used for different wave length for some spectrogrph with the corresponding output signal of intensity of the ray that is received is provided;
The device of content that is used for quantitatively determining to be included at least a material of dispersion liquid or solution according to described output signal.
12. the device according to claim 11 is characterized in that, described spectrogrph has the device of wavelength to detect by a photodiode arrangement that is used for the reception ray is divided into some.
13. the device according to claim 11 or 12 is characterized in that, described irradiation source is hydrargyrum-Halogen light.
14. the device according to claim 11 or 12 is characterized in that, described device also adds has optical fiber, and described optical fiber will conduct to described product place by the ray of irradiation source emission.
15. the device according to claim 11 or 12 is characterized in that, described ray receiving system has convex lens and optical fiber.
16. the device according to claim 11 or 12 is characterized in that, described quantitatively definite device utilizes weight coefficient.
17. the device according to claim 16 is characterized in that, obtains the weight coefficient adopted based on solution, the solution that is used to obtain weight coefficient contains identical pending quantitatively definite material with dispersion liquid.
18. the device according to claim 11 or 12 is characterized in that, described device also additionally has calibrating installation, utilizes described calibrating installation can determine the quantitative levels of described at least a material by another kind of method.
19. the device according to claim 18 is characterized in that, described calibrating installation comprises the enforcement high pressure lipuid chromatography (HPLC).
20. the device according to claim 11 or 12 is characterized in that, described device also additionally comprises and is used to sub-elect the not sorting unit of the product within predetermined whole standard.
21. the device according to claim 11 or 12 is characterized in that, described device is used to make the device for the treatment of quantitative dispersion liquid homogenization also additional comprising.
22. the device according to claim 11 or 12 is characterized in that, described device additionally comprises a device that is used to discern product space.
23. according to the application of claim 11 or 12 devices that limited, being used for is being that the solution of purpose or manufacturing, filling and/or the packaging process of dispersion liquid carry out quality control to product unit with the pharmacy.
24. be used to load the filling device of solution and dispersion liquid, comprise according to each device in the claim 11 to 22.
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| DE10326152A DE10326152A1 (en) | 2003-06-06 | 2003-06-06 | Method and device for the quantitative analysis of solutions and dispersions by means of near-infrared spectroscopy |
| DE10326152.4 | 2003-06-06 |
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| JP (1) | JP5007118B2 (en) |
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| UA (1) | UA90847C2 (en) |
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| DE202007001444U1 (en) | 2007-01-31 | 2008-06-12 | Seidenader Maschinenbau Gmbh | Apparatus for testing insulin-filled containers |
| DE102008037713A1 (en) | 2008-08-14 | 2010-02-18 | Systektum Gmbh | Apparatus and method for concentration analysis of the contents of drug-filled glass containers |
| WO2013113388A1 (en) * | 2012-02-02 | 2013-08-08 | Foss Analytical A/S | Method of controlling a production process |
| CN104062258B (en) * | 2013-05-07 | 2017-02-22 | 山东东阿阿胶股份有限公司 | Method for rapid determination of soluble solids in compound ass-hide glue pulp by near infrared spectroscopy |
| SG11201600306XA (en) * | 2013-07-19 | 2016-02-26 | Wilco Ag | Method of in-line testing devices and testing apparatus |
| CN113477149B (en) | 2013-11-06 | 2023-09-12 | 贝克顿·迪金森公司 | Microfluidic devices and methods of making and using the same |
| CN105899936B (en) | 2013-11-13 | 2019-12-24 | 贝克顿·迪金森公司 | Optical imaging system and method of using the same |
| KR101697499B1 (en) | 2015-11-16 | 2017-01-19 | 세메스 주식회사 | Unit for supplying liquid and Apparatus for treating substrate with the unit |
| KR101977757B1 (en) | 2017-05-10 | 2019-05-14 | 세메스 주식회사 | Apparatus for treating substrate |
| KR101977771B1 (en) | 2017-05-10 | 2019-05-14 | 세메스 주식회사 | Apparatus for treating substrate |
| EP3499219B1 (en) * | 2017-12-14 | 2020-08-05 | Medios Manufaktur GmbH | Method and device for operating a ready-made medication |
| CN110887809B (en) * | 2018-09-07 | 2022-07-12 | 湖南中烟工业有限责任公司 | Method for measuring stem content in tobacco shreds based on near infrared spectrum technology |
| EP4031852A1 (en) * | 2020-01-17 | 2022-07-27 | Rodriguez Garcia, Laura | Method for identifying the quality of a liquid pharmaceutical product |
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2003
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2004
- 2004-05-22 CA CA2528373A patent/CA2528373C/en not_active Expired - Fee Related
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1214768A (en) * | 1996-02-02 | 1999-04-21 | 量度测试设备股份有限公司 | Method and apparatus for multi-spectral analysis in nonvinvasive infrared spectroscopy |
| EP0887638A1 (en) * | 1997-06-24 | 1998-12-30 | The Automation Partnership (Cambridge) Limited | Product integrity verification apparatus |
| WO2001016578A1 (en) * | 1999-08-31 | 2001-03-08 | Cme Telemetrix Inc. | Method for determination of analytes using near infrared, adjacent visible spectrum and an array of longer near infrared wavelengths |
| CN2393064Y (en) * | 1999-11-22 | 2000-08-23 | 孙勇 | Plate-type heat-pipe radiator |
| US20020109094A1 (en) * | 2001-02-12 | 2002-08-15 | Alexander Goetz | System and method for combining reflectance data |
Also Published As
| Publication number | Publication date |
|---|---|
| CY1114655T1 (en) | 2016-12-14 |
| IL172371A (en) | 2011-04-28 |
| DK1635698T3 (en) | 2013-12-09 |
| NZ543961A (en) | 2008-11-28 |
| SI1635698T1 (en) | 2013-12-31 |
| EP1635698A1 (en) | 2006-03-22 |
| CN1802120A (en) | 2006-07-12 |
| RU2005141437A (en) | 2006-09-10 |
| PL1635698T3 (en) | 2014-03-31 |
| HK1089919A1 (en) | 2006-12-15 |
| UA90847C2 (en) | 2010-06-10 |
| NO20060042L (en) | 2006-01-04 |
| DE10326152A1 (en) | 2005-01-05 |
| RU2395073C2 (en) | 2010-07-20 |
| WO2004107969A1 (en) | 2004-12-16 |
| CA2528373C (en) | 2013-10-29 |
| AU2004244713A1 (en) | 2004-12-16 |
| MXPA05012660A (en) | 2006-08-23 |
| EP1635698B1 (en) | 2013-08-28 |
| JP2006527358A (en) | 2006-11-30 |
| BRPI0410988A (en) | 2006-07-04 |
| JP5007118B2 (en) | 2012-08-22 |
| KR20060037266A (en) | 2006-05-03 |
| PT1635698E (en) | 2013-10-22 |
| ES2435042T3 (en) | 2013-12-18 |
| CA2528373A1 (en) | 2004-12-16 |
| AU2004244713B2 (en) | 2009-06-11 |
| NO338611B1 (en) | 2016-09-12 |
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